ROLE OF CYTOCHROME P4502E1-DEPENDENT FORMATION OF HYDROXYETHYL FREE-RADICAL IN THE DEVELOPMENT OF LIVER-DAMAGE IN RATS INTRAGASTRICALLY FEDWITH ETHANOL

We have previously shown that the treatment with diallyl sulfide (DAS) and phenylethyl isothiocyanate (PIG) of rats receiving ethanol in the alcohol tube-feeding model effectively suppressed the induction of cy tochrome P4502E1 (CYP2E1) by ethanol, Here we report that rat treatmen t with DAS and PIC significantly decreased the trapping of hydroxyethy l free radicals in Liver microsomes incubated in vitro with ethanol. F urthermore, these inhibitors also greatly reduced the production of hy droxyethyl radical derived epitopes detectable in vivo in the liver of ethanol-fed rats. The action of DAS and PIC on the formation of hydro xyethyl radicals paralleled their inhibitory effect on lipid peroxidat ion as monitored using, respectively, liver malonildialdehyde (MDA) an d plasma lipid hydroperoxide levels as well as by the titers of antibo dies versus MDA adducts to proteins, Thus, these results indicated a L ink between the induction of CYP2E1 by ethanol, the formation of hydro xyethyl radicals and the stimulation of lipid peroxidation, The pathol ogical scores in the Livers of rats fed with ethanol plus or minus DAS and PLC also correlated with levels of hydroxyethyl radical-derived e pitopes, Rats fed intragastrically with ethanol developed antibodies r eacting with hydroxyethyl radicals-modified proteins and the formation of these antibodies was greatly reduced by DAS and PIG. Taken togethe r these results suggest that CYP2E1 plays an important role in the gen eration of hydroxyethyl radicals during chronic alcohol feeding and th at ethanol-derived free radicals might play a role in the onset of Liv er injury in this model of alcohol administration.